Compounds related to the compounds of the present invention are known from DE patent application No. 4414113 describing certain 4-(indol-3-yl)-1-(indol-3-yl-alkylene)-piperidines. The compounds herein are claimed to show serotonin antagonistic and agonistic activities and to have effect on DOPA-accumulation in striatum. No biological data are given.
GB patent application No. 2 044 254 describes certain 1-(indol-3-yl-alkylene)-piperidine derivatives which are substituted in position 3 or 4 of the piperidine ring with an isoindole, or an isoquinoline ring. These compounds are claimed to have 5-HT reuptake inhibiting activity and to be useful as antidepressants.
Furthermore, in WO patent publications No. WO 9421627, WO 9421630 and WO 94 21626 various series of indolyl- or indazolylmethyl piperidine or piperazine derivatives are described to be selective dopamine D.sub.4 antagonists. No data are given. The compounds are only said to give K.sub.i values of less than 1.5 .mu.M in a test for displacement of .sup.3 H spiperone from human dopamine D.sub.4 receptor subtypes in clonal cell lines.
WO patent publication No. 95/33721 relates to 1-(indanemethyl, dihydrobenzofuranylmethyl, or dihydrobenzothiophenylmethyl)piperidine, -tetrahydropyridine, or piperazine derivatives. The 1-indanemethyl compounds disclosed herein are substituted in position 6 with an amino containing group. The compounds interact with central 5-HT receptors, in particular with 5-HT.sub.1A and 5-HT.sub.2A receptors. Some of the compounds are said to have 5-HT reuptake inhibiting effect.
Dopamine D.sub.4 receptors belong to the dopamine D.sub.2 receptor family which is considered to be responsible for the antipsychotic effects of neuroleptics. Dopamine D.sub.4 receptors are primarily located in areas of the brain other than striatum (Van Tol, et al. Nature, 1991, 350, 610). The low level of D.sub.4 receptors in striatum suggesting that compounds which are selective for the dopamine D.sub.4 receptor will be devoid of extrapyramidal activity, is illustrated by the antipsychotic clozapine which has a high affinity for dopamine D.sub.4 receptors and is lacking extrapyramidal side effects, (Van Tol, et al. Nature, 1991, 350, 610). Also, dopamine D.sub.4 receptor levels have been reported to be elevated in schizophrenic patients (Seeman et al., Nature, 1993, 365, 441.).
Various effects are known with respect to compounds which are ligands at the different serotonin receptor subtypes. As regards the .sup.5 -HT.sub.2A receptor, which was previously referred to as the 5-HT.sub.2 receptor, the following effects have e.g. been reported:
Antidepressive effect and improvement of the sleep quality (Meert, T. F.; Janssen, P. A. J. Drug. Dev. Res. 1989, 18, 119.) reduction of the negative symptoms of schizophrenia and of extrapyramidal side-effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders, Y. G., British J. Psychiatry, 1989, 155 (suppl. 5, 33). Finally, selective 5-HT.sub.2A antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; "Migraine--Current trends in research and treatment"; PJB Publications Ltd.; May 1991).
Clinical studies have shown that 5-HT.sub.1A partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate that full agonists are useful in the treatment of the above mentioned anxiety related disorders (Schipper, Human Psychopharmacol., 1991, 6, S53).
There is evidence, both clinical and preclinical, in support of the beneficial effect of 5-HT.sub.1A partial agonists in the treatment of depression, impulse control disorders and alcohol abuse (van Hest, Psychopharmacol., 1992, 107, 474; Schipper et al, Human Psychopharmacol., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz and Poh, Drugs 1991, 41, 11; Grof et al., Int. Clin. Psychopharmacol. 1993, 8, 167-172; Ansseau et al., Human Psychopharmacol. 1993, 8, 279-283).
5-HT.sub.1A agonists and partial agonists inhibit isolation-induced aggression in male mice indicating that these compounds may be useful in the treatment of aggression (Sanchez et al. Psychopharmacology, 1993, 110, 53-59).
Furthermore, 5-HT.sub.1A ligands have been reported to show antipsychotic effect in animal models (Wadenberg and Ahlenius, J. Neural. Transm., 1991, 83, 43; Ahlenius, Pharmacol.&Toxicol., 1989, 64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147; and Martin et al., J. Med. Chem., 1989, 32, 1052).
Recent studies also indicate that 5-HT.sub.1A receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609, Wadenberg et al. Pharmacol.Biochem. & Behav. 1994, 47, 509-513) suggesting that 5-HT.sub.1A agonists are useful in the treatment of extrapyramidal side-effects induced by conventional antipsychotic agents such as haloperidol.
5-HT.sub.1A agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn, Eur. J. Pharm. 1991, 203, 213).
Pharmacological studies have been presented which indicate that 5-HT.sub.1A antagonists are useful in the treatment of senile dementia (Bowen et al, Trends Neur. Sci. 1992, 15, 84).
5-HT reuptake inhibitors are well known antidepressant drugs.
Accordingly, dopamine D.sub.4 receptor ligands are potential drugs for the treatment of psychoses and positive symptoms of schizophrenia and compounds with combined effects at dopamine D.sub.4 and 5-HT receptors and/or the 5-HT transporter may have the further benefit of improved effect on other psychiatric symptoms in schizophrenic patients such as depressive and anxiety symptoms. 5-HT.sub.1A and 5-HT.sub.2A receptor ligands and 5-HT reuptake inhibitors have different activities in different animal models predictive of anxiolytic and antiaggressive effects (Perregaard et al., Recent Developments in Anxiolytics. Current Opinion in Therapeutic Patents 1993, 1, 101-128) and/or in models predictive of effects in other psychic disorders and it is considered highly beneficial to have such combined serotonergic effects.
Compounds with dopamine D.sub.4 receptor activity combined with effect at 5-HT receptors and compounds with dopamine D.sub.4 receptor activity combined with 5-HT reuptake inhibiting effect is considered a new therapeutic approach in the treatment of neurologic and psychiatric disorders, including in particular psychosis.